Abstract: Brucella infections can cause debilitating disease with relapses of an undulating fever and lifelong complications, including arthritis, endocarditis, and possible neurological complications, even with antibiotic treatment. Moreover, in many parts of the world, brucellosis remains problematic, and it is estimated that approximately 500,000 new cases occur annually, making brucellosis one of the most common zoonotic diseases globally. In humans, Brucella spp. causes a chronic infection that in some cases may be lifelong and permanently debilitating. However, mechanisms underlying Brucella?s ability to cause chronic infection remain largely unknown. The overall goal of this project is to better understand the role of B cells in the pathogenesis of chronic brucellosis. In our preliminary data, we found that B cells contained >90% of viable, recoverable, intracellular Brucella from infected wild-type mouse spleens. In the proposed studies, we will investigate the role of B cells as a reservoir of chronic Brucella infection and determine what genes Brucella requires to chronically infect B cells in vivo. In Aim #1 of this proposal we will determine what splenic B cell subsets harbor viable Brucella during acute and chronic infection. The role of specific B cell subsets (B1a and marginal zone B cells) in the pathogenesis of chronic brucellosis will also be assessed. In addition, we will determine if Brucella residing in B cells are resistant to T cell and/or vaccine-mediate immunity. In Aim #2 we will determine what Brucella genes are required to persistently colonize B cells in vivo. Collectively, our results will enhance our knowledge of the pathogenesis of chronic brucellosis and should also have implications for future rational design of Brucella vaccines.